The immune system protects a subject from possibly harmful substances by recognizing and responding to antigens. Antigens are substances, typically peptides, on the surface of cells, viruses, fungi, or bacteria. Nonliving substances such as toxins, chemicals, drugs, and foreign particles can also be antigens. The immune system recognizes and destroys substances that contain antigens. An epitope, also referred to as an antigenic determinant, is a portion of an antigen that is recognized by various molecules and cells that make up a subject's immune system (e.g., antibodies, T cells, B cells). An epitope is a specific peptide region of the antigen to which an antibody binds. T-cell epitopes, for example, are presented on the surface of antigen-presenting cells where they are typically bound to MEW molecules (major histocompatibility complex). An immune response is initiated following T cell recognition of antigen peptides in the context of self MEW molecules, and generally takes place in one of the host's secondary lymphoid compartments. Cellular activation is triggered by the binding of antigen to the T cell receptor (TCR), forming an antigen/TCR complex which transduces the antigen-specific extracellular stimulation across the plasma membrane, and generates intracellular signals which include the activation of protein kinase C and the increases in intracellular calcium. While signal transduction can lead to T cell unresponsiveness, positive signal transduction events trigger a series of additional biochemical processes that lead to an immune response in a subject.
One obstacle in the advancement for developing vaccines against pathogens with genetic variability is immune escape. Typically, immune escape involves amino acid substitutions in specific epitopes of a pathogenic antigen recognized by the host immune system (e.g., CTL, Th and B epitopes). Despite the degenerate nature of the interactions between a TCR of T cells and MHC/peptide complex on antigen-presenting cells, the majority of circulating variants are not recognized by CTLs. This may explain the immune system's failure in clearing or containing various pathogens. The ability of pathogens to escape immunity by mutating amino acids in epitopes or flanking regions (affecting the correct epitope processing) is an ongoing and dynamic process involving complex viral-host interactions. Other factors affecting the immune escape phenomenon include viral fitness, cost of mutations, immune pressure exerted by the host, host genetic factors, and viral load.
In the field of cancer epitope vaccines, the modified, optimized or variant peptides, also known as altered peptide ligands (APLs), mimotopes, heteroclitic peptides or peptide analogues, bearing mutated versions of natural epitopes derived from tumor-associated antigens (TAAs) are considered to be promising candidates for the development of vaccines. Comprehensive screening strategies, such as testing virtually every single amino acid substitution within an epitope by genetic screen, may lead to identification of superagonist APLs capable of eliciting potent anti-tumor patient-specific CTL responses when the native or wild type (WT) tumor-associated epitope fails. Central TCR-contact residues of antigenic peptides can be replaced even by non-peptidic units without loss of binding affinity to major histocompatibility complex (MHC) class-I molecules and T-cell triggering capacity. However, there are a very large number of potential epitopes expressed in tumors that are encoded by non-primary open reading frame (ORF) sequences (frame-shift mutations) or derived from other non-traditional sources, such as transcriptional/translational mechanisms or splicing events, collectively referred as epitopes derived from defective ribosomal products (DRiPs).